16alpha-methyl pregnanes



United States Patent 3,069,413 16a-METHY L PREGNANES John A. Zderic andHoward J. Ringold, Mexico City, Mexico, assignors, by mesne assignments,to Syntax Corporation, a corporation of Panama No Drawing. Filed Mar. 8,1960, Ser. No. 13,427 Claims priority, application Mexico Mar. 11, 195912 Claims. (Cl. 260-2395) The present invention relates to a novelmethod for the preparation of 16-methyl-A -pregnene-l7a,21-diol-3,20-dione which is an important intermediate for the preparation of16-methyl cortical hormones.

More particularly the present invention comprises a novel method forhydroxylation at 0-170: of the known16a-methyl-allopregnan-3l3-ol-20-one or of Mot-methylpregnenolone. Priorart methods for introduction of a hydroXyl group at C17a of a16-methyl-pregnan-20-one which involve the formation of the A -enolacetate, followed by treatment with an organic peracid and thensubsequent alkaline treatment of the thus formed 17,20- epoxide do notproceed satisfactorily in the presence of a methyl group at C-16.

In accordance with the present invention, there has is i I "B, i -oH=Toni C-21-accty1ation on l l -CH3 1 -CH3 LiA1H chromic acid 0: I l Hacetate .ifihgAfi Patented Dec 18, 1962 been discovered a novel processfor introduction of a hydroxyl group at C-l7a in high yield and underconditions whereby the process is especially adaptable to large scaleproduction.

It has been discovered that dibromination at C-l7a and 0-21 of a16-methyl-pregnan-20-one-3-ol followed by interchange of the bromine at0-21 by iodine and reaction with an alkali metal lower alkoxide such assodium methoxide, there is obtained the lower alkyl ester, spe- 10cifically the methyl ester, of the respective A -21- carboxylic acidwhich is then reduced to the corresponding alcohol by reaction with adouble metal hydride. Monoacetylation of the resulting 3,21-diol at C-21followed by oxidation of the hydroxyl group at C-3 to the keto group andfurther treatment with phenyliodosoacetate produces the16u-methyl-17a-hydroXy-21-acetoxy compound. Alternatively, the reductionmay follow oxidation of the 3,8-hydroxyl group to the keto group; inthat case the 3-keto group is temporarily protected by 20 formation ofan enamine, and after hydrolysis of the enamine, the A -pregnan-21-ol isacetylated at C-21 and subsequently is treated with phenyliodosoacetate.

The following equation serves to illustrate in part the presentinvention:

Br 1i ICE,

Bromination lNaI COOR CHzI sodium alkoxide alcohol CHzO Ac pyrrolidineLlAlHl NAOAc l henyliodoso OHQOAC 'In the above equation, Ac representsthe acetyl group, R represents a hydrocarbon carboxylic acyl group,preferab-ly an acyl group derived from a lower hydrocarbon carboxylicacid, and R represents lower alkyl.

In practicing the above invention, an ester of16amethyl-allopregnan-ZO-one-3fl-ol, preferably the acetate thereof, istreated with 2 molar equivalents of bromine to form the3,8-acetoxy-lfiu-methyl-d7a,2l-dibromoallopregnan-ZO-one, which is thentreated with sodium iodide in a mixture of benzene and ethanol to obtainSB-acetoxy 16oz methyl-17a-bromo-2l-iodoallopregnan- 20-one. Bysubsequent reaction with an alkali metal alkoxide such as methoxide inmethanol solution, the alkyl ester, specifically the methyl ester of16a-methyl- A -allopregnen-3fl-ol-21-carboxylic acid is obtained whichcan then be oxidized to the methyl ester of 16amethyl-A-3-keto-2l-carboxylic acid [by treatment with 8 N chromic acid. The ketogroup is protected by heating with pyrrolidine in methanol to form thepyrrolidyl-enamine and the resulting methyl ester of 3- pyrrolidyl-16amethyl A -allopregnadiene-2l-carboxylic acid is refluxed with lithiumaluminum hydride in a solvent such as tetrahydrofuran to reduce thecarbomethoxy group to the hydroxymethyl group. Upon subsequenthydrolysis of the enamine group, as by heating with sodium acetate inmixture with methanol and aqueous acetic acid under reflux conditions,there is obtained 16a-methyl-A -allopregnan-21-ol-3-one which is thenacetylated at (1-21 by conventional methods. The resulting compound isthen treated with phenyliodosoacetate in aqueous t-butanol and in thepresence of pyridine and catalytic amounts of osmium tetroxide tofurnish the ZI-acetate of 16ot-methyl-allopregnane-17a,21-diol-3,20-dione which can then be converted by conventional methods, asdisclosed by Rosenkranz et al. in US. Patent 2,703,805 to l6a-methyl-A-pregnene-17ot,21- diol-3,20-dione.

Alternatively the methyl ester of l6umethyl-Aallopregnen-3fi-ol-2l-carboxylic acid can be treated with lithiumaluminum hydride to reduce the C-21 carbomethoxy group to form16a-methyl-A -allopregnene- 3fl,21-diol which is selectively acetylatedat 0-21 by reaction with 1 molar equivalent of acetic anhydride inpyridine solution at low temperature and then is subjected to the actionof 8 N chromic acid to oxidize the C-3 hydroxyl group to the keto groupto thus form the ZI-acetate of 16a-methyl-A -allopregnen-2l-ol- 3-one.Subsequent treatment with phenyliodosoacetate yields the Zl-acetate ofl6a-methyl-allopregnane-1704,21- diol-3,20-dione, identical with thecompound obtained in accordance with the procedure hereinabovedescribed.

The following equation serves to illustrate another portion of thepresent invention:

$113 (llHzBr :0 (3 0 Ai f C H; I C H: Bromination R O R 0 I 1'31- l NaI(I30 0 R (EH 1 CH 0:0 1 m on, Torn sodium alkoxide I alcohol HO R O \JLiAlH C-21-acetylation chromic acid Oppenauer oxidation In the aboveequation, R, R and Ac have the same meanings as heretofore described.

In practicing the process just outlined, an ester of 16cc methyl Apregnen 20 one 36 01, preferably the acetate, is converted into3,8-acetxy-16ot-methyl- 50:,65,l70,2ltetrabromo-pregnan-ZO-one byreaction with 3 molar equivalents of bromine and upon subsequenttreatment with sodium iodide, 3,8-acetoxy-16u-methyl- 170a bromo 21 iodoA pregnen one is obtained. Treatment of the latter with sodium methoxideaffords the methyl ester of 16a-methyl-A -pregnadien-35-ol-2l-carboxylicacid. The hydroxy group at C3 is transformed into the 3-keto group byreaction with 8 N chromic acid. Prior to the reduction of the estergroup at C-2l, the 34mm group of the methyl ester of the 16ot-me-thyl-A-pregnadiene 21-carboxylic acid is protected by formation of apyrrolidyl enamine by heating with pyrrolidine in methanol. The ketogroup may also be protected by the formation of the 3-alkyl enol etheror a cycloalkyleneketal by known methods. The reaction of the methylester of 3-pyrrolidyl-16ocmethyl-A -pregnatriene 21 carboxylic acid withlithium aluminum hydride in the same manner, as set forth previously,results in the formation of 3-pyrrolidyl- 16oc-methyl-A-pregnatrien-Zl-ol, which upon subsequent hydrolysis of the enaminegroup as by treatment with a mixture of acetic acid and sodium acetateaffords 1Gwmethyl-A -pregnadien-21-ol-3-one whose acetate is thensubjected to reaction with phenyliodosoacetate to obtain the ZI-acetateof 16a methyl A -pregnene 17a,2l-dlOl-3,20-dl0l'l.

Alternatively the methyl ester of 16ot-methyl-Apregnadien-3fi-ol-2l-carboxylic acid can be reacted with lithiumaluminum hydride to reduce the carbomethoxy group to the hydroxymethylgroup to thus form 160:- methyl Aimml) pregnadiene 3,6,21 diol.Selective acetylation at C-2l as hereinabove set forth followed byoxidation under Oppenauer conditons results in the formation of 1604methyl [1 pregnadien 21 ol- 3-one acetate which upon treatment withphenyliodosoacetate gives the same 16m-methyl-A -pregnene-17a,21-diol-3,20-dione ZI-acetate obtained by the above procedures.

The latter product is an important intermediate which can be transformedinto the useful l6m-methyl corticoids COOR by introduction of thehydroxyl group at C11 by known dione can be converted into theZI-acetate 16u-methyl- A -pregnadiene-17a,21-diol-3,2O-dione which inturn can further be dehydrogenated at Cl,2 by conventional methods suchas treatment with SeO or by microbiological methods as by incubationwith a micro-organism such as the fungus Streptomyxa afiinis ATCC 6737to form 16a methyl A pregnatriene-17a,21-diol-3,20- dione. The lattercan also be obtained by treating the 21 -acetate of 16a-methyl-A-pregnene-17a,21-diol-3,20- dione with chloranil in mixture with n-amylalcohol under reflux conditions.

By applying the novel process of this invention to 165- methyl 3Bacetoxy allopregnan 20 one and 16,8- methyl-3,8-acetoxy-A-pregnen-20-one, there can be obtained the corresponding16l3-methyl-17u-hydroxy-21- acetoxy compounds.

Example 1 A solution of 50 g. of 3,8acetoxy-16m-methyl-A -pregnen-ZO-onein 500 cc. of glacial acetic acid was treated with 27.4 g. of bromine atroom temperature; a few drops of a solution of dry hydrogen bromide inacetic acid were then added, followed by the slow addition of 44.8 g. ofbromine, with stirring. The mixture was stirred until almost completedecoloraticn, then poured into water and the bromination product wascollected by filtration, washed with water, dried and recrystallizedfrom acetone. There was thus obtained 3fl-acetoxy-16a-methyl-50,6fl,17u,21-tetrabromo-pregnan-ZO-one; M.P. 172174 C.; [a] -[-28(chloroform).

A mixture of 70 g. of the above compound, 240 g. of sodium iodide and 2lt. of equal parts of benzene and ethanol was kept overnight at roomtemperature and then poured into water and extracted with ethyl acetate.The

extract was washed with water, dried over anhydrous sodium sulfate andthe solvent was evaporated. Crystallization of the residue frombenzene-ether aiforded 3flacetoxy 16cc methyl-lh-bromo-Zl-iodo-a-pregnen-20 one; M.P. 165-167 (3.; [a] +68 (chloroform).

To a solution of sodium methoxide prepared by dissolving 15 g. of sodiumin cc. of methanol, was added 20 g. of3,8-acetoxy-16a-methyl-l7a-bromo-21-iodo- A -pregnen-2O-one and themixture was allowed to react overnight at room temperature. Afterpouring into water the product was extracted with ethyl acetate; theextract was washed with dilute hydrochloric acid and then with water,dried over anhydrous sodium sulfate and the ethyl acetate wasevaporated. Crystallization of the residue from ethyl acetate furnishedthe methyl ester of 160L- methyl-A -pregnadien-3B-ol-2l-carboxylic acid;M.P. l66-l69 C.; [a] 70 (chloroform);

A 226-228 mu, log E 4.14

A solution of 14 g. of the above compound in 240 cc. of acetone wascooled to C. and treated under an atmosphere of nitrogen and withcontinuous stirring at 0 C. with an 8 N solution of chromic acid untilthe brown-red color of chromium trioxide persisted in the mixture (the 8N solution of chromic acid had been prepared by dissolving chromiumtrioxide in concentrated sulfuric acid and diluting with water); themixture was then stirred for minutes more at 0 C., diluted with waterand the precipitate was collected, washed with water, dried andrecrystallized from acetone-ether. There was thus obtained the methylester of 16a-methyl- A -pregnadiene-3-keto-2l-carboxylic acid; M.P. 164-166 C.; [M -68 (chloroform);

k 226 my, log E 4.06

To a solution of g. of the above compound in 200 cc. of boiling methanolwas added 10 cc. of pyrrolidine and the mixture was allowed to attainroom temperature; the precipitate was collected, dried andrecrystallized from hexane. There was thus obtained the methyl ester of3-pyrrolidyl-l6a-methyl-A -pregnatriene-2l-carboxylic acid; MP. 175-l77C.; [ab-490 (pyridine);

A553 230, 276280 m log E 4.26, 3.97

A mixture of 8 g. of the above compound, 400* cc. of tetrahydrofuraneand 8 g. of lithium aluminum hydride was refluxed for one hour. Aqueoussaturated sodium sulfate solution was then added, followed by anhydroussodium sulfate; the solid was filtered and the solvent of the filtratewas evaporated. Recrystallization of the residue from hexane-etheryielded 3 pyrrolidyl 16ccmethyl-A -pregnatrien-Z1-ol.

A mixture of 6 g. of the above compound, 16 g. of sodium acetate, 40 cc.of water, 16 cc. of acetic acid and 20 cc. of methanol was refluxed for4 hours and concentrated to a small volume under reduced pressure. Theproduct was extracted with chloroform, the extract was washed withdilute hydrochloric acid and water; and the chloroform was evaporated,recrystallization of the residue from acetone-hexane afforded16rx-methyl- A -pregnadien-21ol-3-one.

A mixture of 4 g. of the above compound, 40 cc. of pyridine and 20 cc.of acetic anhydride was heated on the steam bath for half an hour;afiter pouring into water the mixture was heated for half an hour on thesteam bath, cooled and the precipitate was collected, washed with water,dried and recrystallized from ether-hexane, thus producing the acetateof 16a-methyl-M -pregnadien-2l-ol-3-one.

To a solution of 3 g. of the above compound in 180 cc. of t-butanol and4.5 cc. of pyridine was added a mixture of 30 mg. of osmium tetroxide,cc. of t-butanol and 0.6 cc. of water, followed by slow addition of 7.5g. of phenyliodosoacetate; all these operations were conducted :at roomtemperature and under continuous stirring. The mixture was then stirredfor 5 hours. 60 cc. of water was added and concentrated to a smallvolume under reduced pressure; the product was extractedwith methylenechloride, the extract was washed with water, dried over anhydrous sodiumsulfate and the solvent was evaporated. By chromatography of the residueon Florisil, eluting with mixtures of methylene chloride-acetone (75:25), there was obtained the 21aacetate of 16a-methyl--pregnene-l7a,2l-diol-3,20-dione.

Example 2 There was started from 50 g. of 33-acetoxy-16amethyl-allopregnan--one and essentially the same proceduredescribed in the preceding Example was applied. in the step ofbromination only 2 molar equivalents of bromine were used and there wasobtained Bfl-acetoxy- 16a methyl 170:,21 dibromo allopregnan 20 one; thereaction of the latter with sodium iodide gave 35- acetoxy 16a methyl17a bromo 21 iodo allopregnan-20-one, which was converted by treatmentwith sodium methox-ide into the methyl ester of 16a-methyl- A-allopregnen-3fl-ol-Zl-carboxylic acid, which was in turn oxidized tothe methyl ester of 16a-methyl-A allopregnene-3-keto-2l-carboxylic acid;in the step of enamination there was obtained the methyl ester of the 3pyrrolidyl Ammo) allopregnadiene 21 carboxylic acid, which was reducedby the reaction with lithium aluminum hydride to3-pyrrolidyl-16a-methyl-A allopregnadien-Zl-ol; upon hydrolysis of theenamine group there was obtained l6ot-methyl-A -allopregnen- 21ol-3-one;the latter was acetylated and then subjected to the reaction withphenyliodosoacet-ate to produce the Zl-acetate ofl6a-methyl-tallopregnane-l7ot,21-diol-3,20- dione.

1 g. of the ZI-acetate of 16a-methyl-allopregnane-17a,2l-diol-3,20-dione was dissolved in 10 cc. of glacial acetic acid andtreated with 0.2 cc. of a 4 N solution of dry hydrogen bromide in aceticacid and then with a solution of bromine in acetic acid containingapproximately 2 molar equivalents of bromine, Which addition wasconducted little by little, with stirring :at room temperature. Themixture was heated to 50 C., cooled, kept standing for 2 hours, dilutedwith water and the precipitate was collected, thus giving the crudeZI-acetate of 2,4-dibtomo- 16a methyl allopregnane 170:,21 diol 3,20dione, which was used for the next stage without further purification.

The above crude product was refluxed with 1.5 g. of sodium iodide inmixture with cc. of acetone for 20 hours, then poured into water and thereaction product (2 l-acetate of 16 or-methyl-2-io do-A-pregnene-l7a,21-diol- 3,20-dione) was extracted. The solvent wasevaporated and the residue was dissolved in 60 cc. of dioxane, treatedwith 1.5 g. of sodium bisulfite dissolved in 30 cc. of water and themixture was refluxed for one hour, poured into water and extracted withether; the extract was washed with water, dried over anhydrous sodiumsulfate and the ether was evaporated. Recrystallization of the residuefrom acetone-hexane afforded the ZI-acetate of16umethyl-A4-p-regnene-17a,2l-diol-3,20-dione.

Example 3 In accordance with the method described in- Example 1, themethyl ester of 16or-methyl-A Lallopregnen-3fl-ol- 21-carboxylic acid(cf. Example 2) was treated with lithium aluminum hydride and thus therewas obtained 16a-methy1-A -allopregnene-3 3,21-diol.

To a solution of 5 g. of the above compound in 30 cc.

of pyridine cooled to 0 C. was added 1 molar equivalent of acetic:anhydride and the mixture was kept overmght at 0 C. After pouring intowater the precipitate was collected, Washed with water, dried andrecrystallized from acetone-hexane. There was thus obtained the 21-acetate of 1Gar-methyl-A" -allopregnene-3fi,2l-diol.

By subsequent treatment with 8 N chromic acid, following the methoddescribed in Example 1, there was obtained the ZI-acetate ofl6u-methyl-A -allopregnen- 21-ol-3-one, identical with the intermediateof Example 2.

Example 4 In accordance with the method of Example 1, the methyl esterof 16a-methyl-A -pregnadien-3/3-ol-2l-carboxylic acid, intermediate insuch example, was reacted with lithium aluminum hydride to produce1606-H1BthYl- A -pregnadiene-3,B,2l-diol, which was acetylated to theZI-acetate of 16a-methyl-A -pregnadiene-3fi,21- diol by reaction with 1molar equivalent of acetic anhydride in pyridine solution (cf. Example3).

The traces of moisture were removed from a mixture of 3 g. of the :abovecompound; 400 cc. of toluene and 100 cc. of cyclohexanone, by distilling100 cc. and then 3 g. of aluminum isopropylate in 80 cc. of anhydroustoluene, was added. The mixture was refluxed for 1 hour, diluted withwater and the volatile solvents were removed by steam distillation. Thecooled residue was extracted with ether, the extract was washed withwater, hydrochloric acid solution and again with water until neutral,dried over anhydrous sodium sulfate and the ether was evaporated. Thecrude product was purified by chromatography on neutral alumina.Recrystallization from acetone-hexane of the solid fractions afiordedthe acetate of 1Ga-methyI-M -pregnadien-21-ol-3-one, identical with theintermediate described in Example 1.

Example 5 A solution of 4 g. of the methyl ester of 16u-methy1- A-pregnadiene-3-keto-2l-carboxylic acid (cf. Example 1) in 20 cc. ofdioxane was treated with 4 cc. of ethyl orthoforrnate and 0.5 cc. of asolution prepared by dissolving 4.88 g. of p-toluenesulfonic acid in amixture of 5.4 cc. of dioxane and 1.1 cc. of ethanol; the mixture wasstirred at room temperature for 80 minutes, 1.5 cc. of pyridine was thenadded and the solvent was evaporated to dryness under reduced pressure.Recrystallization of the residue from methanol yielded the methyl esterof 16rx-methyl-3-ethoxy-A -pregnatriene-Z1- carboxylic acid, M.P.151-153 C.; [a] 73.5 (chloroform); A 234 m log E 4.51.

By subsequent reaction with lithium aluminum hydride, as described inExample 1, there was obtained 3-ethoxy- 16a-methyl-A -pregnatrien-21-ol;M.P. 105-107 C.; [a] 120 (chloroform);

N 240242 my, log E 4.26

max.

Example 6 By treatment of a solution of 1 g. of 3-ethoxy-16amethyl-A-pregnatrien-Zl-ol, of the preceding example, with 1 cc. of acetic:anhydride in solution in 10 cc.

10 of pyridine overnight, followed by the usual work up andrecrystallization from hexane, there was obtained the 21- acetate of3-ethoxy-16a-methyl-A -pregnatrien-21-ol in pure form; M.P. 86-88 C.;

R 240-242 mu, log E 4.24

By subsequent hydrolysis of the ethoxy group as described in thepreceding example, there was obtained the 21- acetate of 16a-methy1-A-pregnadien-21-ol-3-one, identical with the intermediate productdescribed in Example 1.

We claim:

1. The lower alkyl esters of 16a-methyl-A-pregnadien-3-one-2l-carboxylic acid.

2. The lower alkyl esters of 3-pyrrolidy'1-1Got-methyl- A-pregnatriene-21-carboxylic acid.

3. The lower alkyl esters of 3-ethoxy-16ot-methy1- A-pregnatriene-2l-carboxylic acid.

4. 3-pyrrolidyl-l6u methyl [E pregnatrien- 21-01.

5. 3'ethoXy-16oc-methyl-A -pregnatrien-2l-ol.

6. The acetate of 3-ethoxy-l6a-methyl-A -pregnatrien-21-ol.

7. 3B-acetoxy-16ot-methyl 1711,21 dibromo allopregnan-20-one.

References Cited in the file of this patent UNITED STATES PATENTS2,305,727 Miescher et a1. Dec. 22, 1942 2,359,773 Marker et a1. Oct. 10,1944 2,667,498 Julian et a1 Jan. 26, 1954 2,982,776 Chamberlein et a1.May 2, 1961 OTHER REFERENCES Marker et al.: J.A.C.S. 64, 1280 (1942).

Disclaimer 3,069,413.-J0/m A. Zdem'o, and Howa rd J. Ringold, MexicoCity, Mexico. Disclaimer the assignee, Symfezo Oomomtion Isa-METHYLPREGNANES. Patent dated Dec. 18, 1962. filed Mar. 16, 1964, by theinventors asse nting.

Hereby enter this disclaimer to claim 11 of said patent.

[Ofiioial Gazette June 2, 1964.]

1. THE LOWER ALKYL ESTERS OF16A-METHYL-$5,17(20)-PREGNADIENE-3-ONE-21-CARBOXYLIC ACID. 4.3-PYRROLIDYL-16A - MEHYL - $3,5,17(20) - PREGNATRIEN21-OL.